Born in Paris of a noble family of Maine. His father was an avocat at the parlement of Paris and author of a curious treatise on the functions of ambassadors, entitled Legatus, seu De legatorum primlegiis, officio et munere libellus (1579) and illustrated mainly from ancient history. Francois succeeded his father at the parlement, but gave up his post about 1647 and devoted himself to travel and belles lettres.
His Considerations sur l'éloquence française (1638) procured him admission to the Académie française, and his De l'instruction de Mgr. le Dauphin (1640) attracted the attention of Richelieu. In 1649 Anne of Austria entrusted him with the education of her second son and subsequently with the completion of Louis XIV's education, which had been very much neglected. The outcome of his pedagogic labors was a series of books comprising the Géographie, Rhétorique, Morale, Economique, Politique, Logique, and Physique du prince (1651-1658). The king rewarded his tutor by appointing him historiographer of France and councillor of state. La Mothe-Le-Vayer died in Paris.
Modest, sceptical, and occasionally obscene in his Latin pieces and in his verses, he made himself a persona grata at the French court, where libertinism in ideas and morals was hailed with relish. Besides his educational works, he wrote Jugement sur les anciens et principaux historiens grecs et latins (1646); a treatise entitled Du peu de certitude qu'il y a en histoire (1668), which in a sense marks the beginning of historical criticism in France; and sceptical Dialogues, published posthumously under the pseudonym of Orosius Tubero. An incomplete edition of his works was published at Dresden in 1756-1759.